Development of a Novel CD26-Targeted Chimeric Antigen Receptor T-Cell Therapy for CD26-Expressing T-Cell Malignancies
Eiji Kobayashi,
Yusuke Kamihara,
Miho Arai,
Akinori Wada,
Shohei Kikuchi,
Ryo Hatano,
Noriaki Iwao,
Takeshi Susukida,
Tatsuhiko Ozawa,
Yuichi Adachi,
Hiroyuki Kishi,
Nam H. Dang,
Taketo Yamada,
Yoshihiro Hayakawa,
Chikao Morimoto,
Tsutomu Sato
Affiliations
Eiji Kobayashi
Department of Immunology, Faculty of Medicine, Academic Assembly, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan
Yusuke Kamihara
Department of Hematology, Faculty of Medicine, Academic Assembly, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan
Miho Arai
Department of Pediatrics, Faculty of Medicine, Academic Assembly, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan
Akinori Wada
Department of Hematology, Faculty of Medicine, Academic Assembly, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan
Shohei Kikuchi
Department of Hematology, Faculty of Medicine, Academic Assembly, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan
Ryo Hatano
Department of Therapy Development and Innovation for Immune Disorders and Cancers, Graduate School of Medicine, Juntendo University, 2-1-1, Hongo, Bunkyo-ku, Tokyo 113-8421, Japan
Noriaki Iwao
Department of Hematology, Juntendo University Shizuoka Hospital, Izunokuni City, Shizuoka 410-2211, Japan
Takeshi Susukida
Division of Host Defences, Institute of Natural Medicine, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan
Tatsuhiko Ozawa
Department of Immunology, Faculty of Medicine, Academic Assembly, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan
Yuichi Adachi
Department of Pediatrics, Faculty of Medicine, Academic Assembly, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan
Hiroyuki Kishi
Department of Immunology, Faculty of Medicine, Academic Assembly, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan
Nam H. Dang
Division of Hematology/Oncology, University of Florida, Gainesville, FL 32610-0275, USA
Taketo Yamada
Department of Pathology, Saitama Medical University, 38 Morohongo, Moroyama, Saitama 3500495, Japan
Yoshihiro Hayakawa
Division of Host Defences, Institute of Natural Medicine, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan
Chikao Morimoto
Department of Therapy Development and Innovation for Immune Disorders and Cancers, Graduate School of Medicine, Juntendo University, 2-1-1, Hongo, Bunkyo-ku, Tokyo 113-8421, Japan
Tsutomu Sato
Department of Hematology, Faculty of Medicine, Academic Assembly, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan
Chimeric-antigen-receptor (CAR) T-cell therapy for CD19-expressing B-cell malignancies is already widely adopted in clinical practice. On the other hand, the development of CAR-T-cell therapy for T-cell malignancies is in its nascent stage. One of the potential targets is CD26, to which we have developed and evaluated the efficacy and safety of the humanized monoclonal antibody YS110. We generated second (CD28) and third (CD28/4-1BB) generation CD26-targeted CAR-T-cells (CD26-2G/3G) using YS110 as the single-chain variable fragment. When co-cultured with CD26-overexpressing target cells, CD26-2G/3G strongly expressed the activation marker CD69 and secreted IFNgamma. In vitro studies targeting the T-cell leukemia cell line HSB2 showed that CD26-2G/3G exhibited significant anti-leukemia effects with the secretion of granzymeB, TNFα, and IL-8, with 3G being superior to 2G. CD26-2G/3G was also highly effective against T-cell lymphoma cells derived from patients. In an in vivo mouse model in which a T-cell lymphoma cell line, KARPAS299, was transplanted subcutaneously, CD26-3G inhibited tumor growth, whereas 2G had no effect. Furthermore, in a systemic dissemination model in which HSB2 was administered intravenously, CD26-3G inhibited tumor growth more potently than 2G, resulting in greater survival benefit. The third-generation CD26-targeted CAR-T-cell therapy may be a promising treatment modality for T-cell malignancies.
